Derivatives of decarbamoyl mitomycin

ABSTRACT

8A,8B-OCTAHYDROAZIRINO(2&#39;&#39;,3&#39;&#39;:3,4)PYRROLO(1,2-A)INDOLE   1-Z,4,7-DI(O=),5-(CH3-),6-X,8-(R-SO3-CH2-)-1,1A,2,4,7,8,   COMPOUNDS OF THE FORMULA AND A PROCESS FOR THEIR PREPARATION ARE PROVIDED WHEREIN X IS METHOXY OR AMINO, Y IS METHOXY OR HYDROXY, Z IS METHYL OR R1CO, R1 IS LOWER ALKYL AND R2 IS LOWER ALKYL OR AROMATIC. THESE COMPOUNDS ARE ANTIBITOTICS.

United States Patent O 3,629,283 DERIVATIVES F DECARBAMOYL MITOMYCIN Keizo Uzu, Kinichi Nakano, and Toshinaka Takahashi, Tokyo-to, .lapan, assignors to Kyowa Hakko Kogyo Kabushiki Kaicha, Tokyo-to, .lapan Filed July 8, 1969, Ser. No. 839,920 Claims priority, application Japan, `Iuly 24, 1968, 43/S1,866 Int. Cl. C07d 27 /36 ILS. Cl. 2611-3263 Claims ABSTRACT 0F THE DISCLOSURE Compounds of the formula and a process for their preparation are provided wherein X is methoxy or amino, Y is methoxy or hydroxy, Z is methyl or RICO, R1 is lower alkyl and R2 is lower alkyl or aromatic. These compounds are antibiotics.

BACKGROUND 0F THE INVENTION AND DESCRIPTION `OF THE PRIOR ART Mitomvcins of the formula CHzOCONHg o Il CHzOH (II) wherein X is methoxy or amino, Y is methoxy or hydroxy and Z is hydrogen or methyl is disclosed in our copending yapplication Ser. No. 814,278, led Apr. 8, 1969. The compounds of Formula II will generically be referred to herein as decarbamoyl mitomycins. Our copending application Ser. No. 814,278 discloses a process for preparing these decarbamoyl mitomycins wherein a mitomycin of Formula I is reacted with an alkali metal alcoholate in an organic solvent. The alcoholate of a primary, secondary or tertiary alcohol may be employed as a nucleophilic reagent in an organic solvent (e.g., alcohol, tetrahydrofuran, dioxane, dimethylformamide, benzene). The reaction is preferably carried out at ambient temperature. Dry Ice in excess of the quantity necessary to neutralize the solution 3,629,283 Patented Dec. 21, 1971 is added to the reaction mixture to neutralize excess alkali and the reaction mixture is then concentrated in vacuo. The residue obtained after concentration is combined with acetone to extract the reaction product. The extract is concentrated and then puried, for example, by using silica-gel chromatography to obtain crystalline a decarbamoyl mitomycin of Formula II.

A process for preparing derivatives of the mitomycins of Formula Il of the formula (III) wherein X is methoxy or amino, Y is methoxy or hydroxy, Z is methyl or RICO and R and R1 are each lower alkyl is disclosed in our copending application Ser. No. 814,278. These acyl derivatives of decarbamoyl mitomycins of Formula II are prepared by subjecting the decarbamoyl mito mycins of Formula II to acylation to convert the CHZOH group at the 9-position into a CHZOCOR group wherein R is lower alkyl. Acylation is conducted by dissolving a decarbamoyl mitomycin of Formula II in a suitable solvent and adding an acid halide or acid anhydride or by condensing a decarbamoyl mitomycin of Formula II with lower carboxylic acid in the presence of a dehydrating condensing agent such as dicyclohexylcarbodiimide. Excess organic base is added to the reaction mixture for the purpose of preventing the decomposition of the reaction product by acid which may be formed during the acylation reaction.

DESCRIPTION OF THE INVENTION X- CHZOH l Y CH3 N/ O NZ wherein X is methoxy or amino, Y is methoxy or hydroxy, Z is methyl or RICO and R1 is lower alkyl is rst prepared by subjecting a compound of Formula II to partial acylation or which is conducted in mild condition.

A compound of the formula cmosozrt,

wherein X is methoxy or amino, Y is methoxy or hydroxy, Z is methyl or RlCO, R1 is lower alkyl and R2 is lower alkyl or aromatic is produced by reacting a cornpound of Formula IV with a sulfonation agent in the presence of a base.

The sulfonation reaction involves the steps of dissolving a compound of Formula IV in a suitable solvent (e.g., water, alcohol, tetrahydrofuran, benzene, pyridine, chloroform, dimethyl formamide) and reacting with a sulfonation agent such as a sulfonic acid halide (e.g., a lower alkyl sulfonic acid halide or a lower alkyl substituted phenyl sulfonic acid halide) in the presence of an excessively large amount of an organic or inorganic base such as sodium bicarbonate at ambient temperature or with ice-cooling. In carrying out the reaction, an excessively large amount of the base should be used in order to prevent the decomposition of the reaction materials by acids which may be produced in the reaction mixture.

The reaction time may vary depending upon the amount of the base used and the property and amount of the sulfonation agent. For example, when tosylation is carried out using7 p-toluene sulfonic acid chloride in anhydrous pyridine, the reaction mixture should be allowed to stand for a night in a cool room.

The obtained compounds of Formula V have strong antibiotic activity as exemplified in Table 1 and are important as intermediates for the synthesis of various lposition substituted derivatives.

Table 1 discloses the antibiotic activity of a representative compound of Formula V wherein X is amino, Y is methoxy, Z is as indicated and R is p-methyl phenyl. The table sets forth the minimum concentration of the compound of Formula V in 'y/ml. of solution necessary to inhibit the growth of three representative types of pathogenic bacteria.

TABLE 1 Bacteria Bacillus subtilis (ATCC 6633) Bacillus magatherum (ATCC 15177). Escherichia coli (ATCC 14948) Preparation of the tosyl derivative of la-acetyl decarbamoyl mitomycin C (X=NH2, Y=OCH3, Z: COCH3 in Formula V) One hundred (100) milligrams of la-acetyl decarbamoyl mitomycin C (X=NH2, Y=OCH3 and Z=COCH3 in Formula IV) were dissolved in 5 ml. of anhydrous pyridine and combined with 100 mg. of p-toluene sulfonyl chloride. The mixture was allowed to stand for a night at 5 C. After this, the reaction mixture was combined with ice water and then combined with an excess amount (5 g.) of sodium bicarbonate. Subsequently, the aqueous solution was extracted with ethyl acetate and the extract was washed several times with saline-saturated water The extract was dehydrated with anhydrous sodium sulfate and was ltrated. The ltrate was concentrated in vacuo to dryness. T he resultant powder gave a single spot and had the infra-red spectrum shown in FIG. 1.

and

EXAMPLE 2 Preparation of the tosyl derivative of la-methyl de- 4 carbamoyl mitomycin C (X=NH2, Y=OCH3, Z=CH3 and in Formula V) One hundred milligrams of decarbamoyl poriromycin (X=NH2, Y=OCH3 and Z=CH3 in Formula IV) were dissolved in 5 ml. of anhydrous pyridine and combined with 100 mg. of p-toluene sulfonyl chloride. The mixture was allowed to stand for a night at 5 C. An after-treatment was carried out in a similar manner to that described in Example l. The infrared spectrum of the obtained product is shown in FIG. 2.

EXAMPLE 3 EXAMPLE 4 Preparation ofthe tosyl derivative of decarbamoyl mitomycin B (X=CH3O, Y: OH, Z=CH3 and in Formula V);

Decarbamoyl mitomycin B (X=CH3O, Y=OH and Z=CH3 in Formula IV) was treated in a similar manner to that described in Example 1 to give the tosyl derivative of decarbamoyl mitomycin B.

We claim:

1. A compound of the formula O Il CHZO S OZB;

wherein X is mcthoxy or amino, Y is methoxy or hydroxy, Z is methyl or RlCO, -R1 is lower alkyl and R2 is lower alkyl or a lower alkyl substituted phenyl group.

2. The compound of claim 1 wherein X is amino, Y is mcthoxy, Z is RICO, R1 is methyl and R2 is p-methyl phenyl.

3. The compound of claim 1 wherein X is amino, Y is mcthoxy, Z is methyl and R2 is p-methyl phenyl.

4. The compound of claim 1 wherein X is amino, Y is mcthoxy, Z is methyl and R2 is methyl.

5. The compound of claim 1 wherein X is mcthoxy, Y is hydroxy, Z is methyl and Ris p-methyl phenyl.

References Cited Nollery: Chemistry of Organic Compounds (1965), pp. 314-15.

ALEX MAZEL, Primary Examiner J. A. NARCAVAGE, Assistant Examiner U.S. Cl. X.R. 260-326.5 (B), 999 

